Pancreatic surgery to treat cancer and other conditions is a difficult operation that carries significant risks, both during the procedure and while the patient recovers. Up to half of patients develop serious complications and 2 to 4 percent do not survive the procedure — one of the highest mortality rates for any operation.
One common complication is leakage of fluid from the pancreas after the surgery, often in large amounts that can cause an abscess and lead to infection and sepsis. This leakage doubles the risk of death and results in longer hospital stays while the fluid is drained. Many patients even have to be readmitted to alleviate this grave complication.
Now Memorial Sloan Kettering clinical researchers have shown that a new drug could dramatically reduce the rate of leakage. Patients receiving the drug, pasireotide, in a phase 3 clinical trial had their rate of serious complication due to leakage cut in half, and significantly fewer had to be readmitted to the hospital.
“This could be a major advance that will change the practice of pancreatic surgery, given the complications that still exist,” says surgical oncologist Peter Allen, Associate Director of the David M. Rubenstein Center for Pancreatic Cancer Research, who led the study. “Pancreatic leak is the Achilles’ heel of this operation, and one of the few remaining difficult complications of any surgery.”
Results of the trial were recently published in the New England Journal of Medicine.
Blocking Leakage at the Secretion Source
Pasireotide appears to prevent leakage by binding to receptors in pancreatic cells, blocking the secretion of digestive enzymes. Normally, Dr. Allen explains, these secretions go into the intestine to break down food, but when they leak into the abdominal cavity during or after surgery, they cause serious problems. This abnormal conduit between pancreas and abdominal cavity is called a pancreatic fistula.
“The pancreas can secrete up to a liter of fluid a day, so when that’s leaking into your abdominal cavity, it can build up very fast,” he says. “We have put to drains in to remove the fluid, sometimes through multiple invasive procedures, and it can be months before the fistula will heal.”
Previous studies in the United States and Europe had tried blocking pancreatic secretion with a drug called octreotide, with mixed results. Octreotide does not seem to bind effectively with critical receptors in the pancreas that control secretion, and the drug does not stay active long enough.
Pasireotide, a newer version of this class of drug, was shown in laboratory and animal studies to be superior both in binding and in staying active longer. Manufactured by Novartis, it was already approved by the Food and Drug Administration in 2012 for the treatment of Cushing’s disease, a condition in which pituitary tumors cause the adrenal gland to secrete too much cortisol.
Because of this promise, Dr. Allen and colleagues designed a clinical trial to test whether pasireotide could block pancreatic secretions and prevent leakage. They randomly assigned 300 Memorial Sloan Kettering patients to receive either pasireotide or a placebo, injected twice daily beginning the morning of the surgery and continuing for seven days. The study was double-blinded, meaning that neither patient nor medical staff knew who received the drug.
Results suggested pasireotide is effective at blocking secretion and reducing complications. Of the 300 patients in the study, the researchers focused on the 45 who had pancreatic leakage, and within this group noted whose leakage was severe enough to require insertion of a drain. Patients receiving the drug required this intervention at a lower rate (9 percent) than those who received the placebo (21 percent). Those receiving the drug were also less likely to need hospital readmission. The pasireotide group had a readmission rate of 17 percent compared with a rate of 29 percent for the placebo group.
“Avoiding readmission is going to significantly reduce cost of care for any patient, in addition to improving quality of life,” Dr. Allen explains. “I’ve already had innumerable surgeons from around the country contacting me [who are] very interested in the effect of this drug and wondering when they will be able to give it to their patients.”
Dr. Allen says that he hopes pasireotide will be eligible for administration outside a clinical trial soon, although this depends partly on the FDA approval process for use in pancreatic surgery. “The placebo and the double-blinding lend a lot of strength to the study and make us feel very confident in the validity of the results,” he says.